PROJECT SUMMARY Metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor (GPCR) highly localized to presynaptic active zones in neurons and its activation reduces glutamate and GABA release. mGlu7 is a member of the group III mGlu receptors, which includes the mGlu4, mGlu6, mGlu7 and mGlu8 receptor subtypes. Polymorphisms in GRM7 have been linked to depression, ADHD, schizophrenia, bipolar disorder, epilepsy, and autism. We have now found that the GRM7 gene is regulated by the transcription factor Methyl CpG Binding Protein 2 (MeCP2). Frameshift or missense mutations in this gene are responsible for 95% of cases of the neurodevelopmental disorder, Rett syndrome (RS), and we observe that mGlu7 protein levels are reduced by approximately 70% in the motor cortex and cerebellum of patients with RS, suggesting that mGlu7 may contribute to the etiology of the disease or may represent a new therapeutic target. At present, there are no selective activator or potentiator tools that target this receptor subtype to explore these possibilities. One prominent phenotype seen in RS and mice deficient in Mecp2 is apneas. Using a nonselective positive allosteric modulator (PAM, VU0422288) with activity at all of the group III mGlu receptors, we can reverse apneas in RS model mice. As VU0422288 is nonselective, we propose to develop a highly selective mGlu7 PAM to validate that mGlu7 potentiation is responsible for apnea reversal. We have made substantial progress in identifying new mGlu7 PAMs and propose to rapidly develop a brain penetrant, selective probe molecule that can be used for chronic dosing. This probe will allow us to definitively test the hypothesis that selective mGlu7 potentiation will reverse apneas in Mecp2-deficient animals. In wild-type mice, we have found that mGlu7 activation at hippocampal Schaffer Collateral-CA1 (SC-CA1) synapses potentiates subthreshold levels of long term potentiation (LTP) and its activation is absolutely required for the induction of LTP via reducing GABA release GABA. The requirement for mGlu7 in the induction of LTP suggests that defects in receptor expression or function may underlie hippocampal-dependent cognitive deficits seen in many neurological and psychiatric disorders, and we propose to use the Rett model to begin to validate the utility of mGlu7 potentiation in the reversal of cognitive deficits. In Mecp2-deficient mice, we can restore synaptic plasticity and hippocampal-mediated task deficits using VU0422288. We propose to use a highly selective PAM probe to determine if these beneficial effects on cognition are due to selective mGlu7 potentiation. We will then expand into other RS domains, such as seizures and motor deficits. We anticipate that the Mecp2-deficient mouse model will serve as an ideal context to validate a selective probe molecule, which will then serve as a critical tool to probe the biology of mGlu7 throughout the brain.